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Although treatment with taxanes does not always lead to clinical benefit, all patients are at risk of their detrimental side effects such as peripheral neuropathy. Understanding the in vivo mode of action of taxanes can help design improved treatment regimens. Here, we demonstrate that in vivo, taxanes directly trigger T cells to selectively kill cancer cells in a non-canonical, T cell receptor-independent manner. Mechanistically, taxanes induce T cells to release cytotoxic extracellular vesicles, which lead to apoptosis specifically in tumor cells while leaving healthy epithelial cells intact. We exploit these findings to develop an effective therapeutic approach, based on transfer of T cells pre-treated with taxanes ex vivo, thereby avoiding toxicity of systemic treatment. Our study reveals a different in vivo mode of action of one of the most commonly used chemotherapies, and opens avenues to harness T cell-dependent anti-tumor effects of taxanes while avoiding systemic toxicity.

Taxus cell cultures are a reliable biotechnological source of the anticancer drug paclitaxel. However, the interplay between taxane production and other metabolic pathways during elicitation remains poorly understood. In this study, we combined untargeted metabolomics and elicited Taxus baccata cell cultures to investigate variations in taxane-associated metabolism under the influence of 1 µM coronatine (COR) and 150 µM salicylic acid (SA). Our results demonstrated pleiotropic effects induced by both COR and SA elicitors, leading to differential changes in cell growth, taxane content, and secondary metabolism. Metabolite annotation revealed significant effects on N-containing compounds, phenylpropanoids, and terpenoids. Multivariate analysis showed that the metabolomic profiles of control and COR-treated samples are closer to each other than to SA-elicited samples at different time points (8, 16, and 24 days). The highest level of paclitaxel content was detected on day 8 under SA elicitation, exhibiting a negative correlation with the biomarkers kauralexin A2 and taxusin. Our study provides valuable insights into the intricate metabolic changes associated with paclitaxel production, aiding its potential optimization through untargeted metabolomics and an evaluation of COR/SA elicitor effects.

The taxane family of microtubule poisons and chemotherapeutics have been studied for over 50 years and are among the most frequently used antineoplastic agents today. Still, limited research exists characterizing taxane-induced sex-specific mechanisms of action and toxicities in cancer and non-cancerous tissue. Such research is important to advance cancer treatment outcomes as well as to address clinically observed sex-differences in short- and long-term taxane-induced toxicities that have disproportionate effects on female and male cancer patients. To gain more insight into these underlying differences between the sexes, the following review draws from pre-clinical and clinical paclitaxel and taxane oncology literature, examines sex-discrepancies, and highlights uncharacterized sex-dependent mechanisms of action and clinical outcomes. To our knowledge, this is the first literature review to provide a current overview of the basic and clinical sex dimorphisms of taxane-induced effects. Most importantly, we hope to provide a starting point for improving and advancing sex-specific personalized chemotherapy and cancer treatment strategies as well as to present a novel approach to review sex as a biological variable in basic and clinical biology.

Background: (Neo-)adjuvant chemotherapy for breast cancer is effective but has deleterious side effects on muscle tissue, resulting in reduced skeletal muscle mass, muscle function, and cardiorespiratory fitness. Various exercise regimens during cancer treatment have been shown to counteract some of these side effects. However, no study has compared the effect of high-intensity training versus low-to-moderate intensity training on muscle tissue cellular outcomes and physical function in patients with breast cancer during chemotherapy. Objective: The aim of this substudy within the Physical Training in Cancer (Phys-Can) consortium is to evaluate and compare the effects of high and low-to-moderate intensity exercise on muscle cellular outcomes, muscle function, and cardiorespiratory fitness in women with breast cancer undergoing (neo-)adjuvant chemotherapy. We further aim to investigate if the effects of chemotherapy including taxanes on muscles will be different from those of taxane-free chemotherapy. Methods: Eighty women recently diagnosed with breast cancer scheduled to start (neo-)adjuvant chemotherapy will be randomized to a combination of strength and endurance training, either at high intensity or at low-to-moderate intensity. Testing of muscle function and cardiorespiratory fitness and collection of muscle biopsies from the vastus lateralis muscle will be performed before the first cycle of chemotherapy (or after 1 week, when not possible) (T0), halfway through chemotherapy (T1), and after completion of chemotherapy (T2). It is estimated that approximately 50% of the participants will be willing to undergo muscle biopsies. To separate the effect of the treatment itself, a usual care group with no supervised training will also be included, and in this group, testing and collection of muscle biopsies will be performed at T0 and T2 only. Results: This study is funded by Active Against Cancer (Aktiv mot kreft) (May 2013) and the Norwegian Cancer Society (December

[Background The aim of this study was to evaluate the impact of certain single-nucleotide polymorphisms (SNPs) in cabazitaxel activity and tox]icity in patients with metastatic castration-resistant prostate cancer (mCRPC)., [Patients & methods] 56 SNPs in five genes (CYP3A4, CYP3A5, ABCB1, TUBB1 and CYP2C8) were genotyped in 67 mCRPC patients and their correlation with outcomes analyzed., [Results]TUBB1-rs151352 (hazard ratio: 0.52) and CYP2C8-rs1341164 (hazard ratio: 0.53) were associated with better overall survival, and CYP2C8-rs1058932 with biochemical progression (odds ratio: 6.60) in multivariate analysis. ABCB1-rs17327624 correlated with severe toxicity ≥grade 3 (odds ratio: 8.56) and CYP2C8-rs11572093 with asthenia (odds ratio: 8.12)., [Conclusion] Genetic variants in mCRPC patients could explain different outcomes with cabazitaxel. Nonetheless, the small sample size and the high number of SNPs analyzed mean that the results are only hypothesis-generating and require further validation.

Purpose: Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer. Methods: We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes. Results: Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95–1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98–1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64–1.07) and mortality (HR: 0.77, 95% CI 0.60–0.98). Conclusion: Docetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help dete

To this day, most preclinical research and clinical use of chemo and radiation cancer therapies do not take sex-differences into consideration, despite women having higher risk of adverse treatment toxicities and making up a larger survivor population than men. Additionally, evolving advances in cancer treatments continue to increase clinical success and there remains a growing unmet need to characterize the long-term toxic effects of frontline therapies, used in both women and men, on cancer survivors’ quality of life. To address these needs, a series of experiments examined the sex-specific effects of paclitaxel, a commonly used taxane family chemotherapeutic, and thoracic radiotherapy treatments on rodents’ cognitive and/or cardiac function. Female and male Wild Type (WT) mice were treated with paclitaxel (150 and 300 mg/kg) administered weekly over 6 weeks or exposed to 19 Gy cardiac irradiation. Systemic, behavioral, and cardiovascular endpoints were examined to assess paclitaxel-induced toxicity and cardiac function and histology were used to assess thoracic radiotherapy-induced toxicity. Interestingly, female WT mice exhibited enhanced tolerance compared to male WT mice in both treatment regimens. To gain more understanding of the observed female-specific protection, RhoB-deficient and aged female WT mice (22 months) were used. RhoB GTPase deficiency was interrogated for the possible impact of sex-hormones in cancer therapy toxicity (RhoB proteins being associated with estrogen receptors in females and cardiac fibrosis in males). In female mice, RhoB deficiency and advanced age had no impact on paclitaxel-induced neurocognitive impairment, but RhoB deficiency did compromise survival after radiotherapy. Conversely, RhoB deficiency reduced paclitaxel-induced neurotoxicity in males and extended male survival after radiation. In summary, this study revealed novel sexually dimorphic toxicities for commonly used taxane and radiation treatments, mediated in-part thr

Thiomers (or thiolated polymers) have broken through as avant-garde approaches in anticancer therapy. Their distinguished reactivity and properties, closely linked to their final applications, justify the extensive research conducted on their preparation and use as smart drug-delivery systems (DDSs). Multiple studies have demonstrated that thiomer-rich nanoformulations can overcome major drawbacks found when administering diverse active pharmaceutical ingredients (APIs), especially in cancer therapy. This work focuses on providing a complete and concise review of the synthetic tools available to thiolate cationic and anionic polymers, in particular chitosan (CTS) and hyaluronic acid (HA), respectively, drawing attention to the most successful procedures. Their chemical reactivity and most relevant properties regarding their use in anticancer formulations are also discussed. In addition, a variety of NP formation procedures are outlined, as well as their use in cancer therapy, particularly for taxanes and siRNA. It is expected that the current work could clarify the main synthetic strategies available, with their scope and drawbacks, as well as provide some insight into thiomer chemistry. Therefore, this review can inspire new research strategies in the development of efficient formulations for the treatment of cancer.

Background: To investigate how socioeconomic position (SEP) influences the effectiveness of cancer-directed treatment in premenopausal breast cancer patients in terms of breast cancer recurrence and mortality. Methods: We conducted a cohort study nested in the ProBeCaRe (Predictors of Breast Cancer Recurrence) cohort (n = 5959). We identified all premenopausal women aged 18–55 years diagnosed with non-metastatic breast cancer and prescribed docetaxel-based chemotherapy in Denmark during 2007–2011. Population-based administrative registries provided data on SEP: marital status (married including registered partnership or single including divorced or widowed), cohabitation (cohabiting or living alone), education (low, intermediate, or high), income (low, medium, or high), and employment status (employed, unemployed, or health-related absenteeism). For each SEP measure, we computed incidence rates, cumulative incidence proportions (CIPs), and used Poisson regression to compute incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of recurrence and death. We stratified on estrogen receptor (ER) status/tamoxifen to evaluate interaction. Results: Our study cohort included 2616 women; 286 (CIP 13%) experienced recurrence and 223 (CIP 11%) died during follow-up (median 6.6 and 7.2 years, respectively). Single women had both increased 5-year risks of recurrence (IRR 1.45, 95% CI 1.11–1.89) and mortality (IRR 1.83, 95% CI 1.32–2.52). Furthermore, we observed increased 5-year mortality in women with low education (IRR 1.49, 95% CI 0.95–2.33), low income (IRR 1.37, 95% CI 0.83–2.28), unemployment (IRR 1.61, 95% CI 0.83–3.13), or health-related work absenteeism (IRR 1.80, 95% CI 1.14–2.82), but smaller or no increased risk of recurrence. These findings were especially evident among women with ER+ tumors prescribed tamoxifen. Overall analyses (follow-up max. 10 years) provided similar results. Conclusions: Low SEP in premenopausal women with non-metastatic breast can

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a recognized adverse effect of standard (neo)adjuvant chemotherapy in breast cancer (BC) treatment. However, there is no consensus on a validated method for assessing CIPN. Heart rate variability (HRV) and vibration perception threshold (VPT) could be used as objective measures to describe CIPN. The aim of this pilot study was to investigate whether subjectively reported CIPN was associated with altered HRV and VPT in BC patients. Methods: We performed a cross-sectional pilot study evaluating 30 BCE patients previously treated with chemotherapy, 26 BCE patients who did not receive chemotherapy, and 22 controls without breast cancer. Self-reported CIPN was registered for the BC patients. All participants were subjected to multi-frequency vibration analyses to determine VPT along with short ECG measurements to determine HRV measures. Results: Self-reported CIPN was registered in 14 (46.6%) BC patients treated with chemotherapy. The VPT at 64 Hz (P = 0.022) and mean HR (P = 0.022) were significantly higher and the HRV measures SDNN (P = 0.023), RMSSD (P = 0.007), LF (P = 0.050) and HF (P = 0.045) were significantly lower in BC patients reporting CIPN compared to controls when adjusted for age. VPT at 64 Hz and 125 Hz were significantly higher in BC patients not reporting CIPN compared to controls when adjusted for age. Conclusion: We found elevated VPT and mean HR along with decreased HRV parameters in 14 BCE patients reporting CIPN. These findings support the need for further investigation into whether HRV and vibration analysis could contribute to an objective assessment of CIPN.

Background: No preferred first-line chemotherapy regimen exists for advanced esophagogastric adenocarcinoma. Addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has been shown to improve survival but is associated with increased toxicity. In this randomized, non-comparative phase 2 trial, we tested carboplatin, docetaxel, and capecitabine (CTX), a potentially useful modification of DCF (NCT02177552). Patients and methods: Patients with advanced HER2-negative esophagogastric adenocarcinoma not previously treated in the first-line setting were randomized to intravenous docetaxel 60 mg/m2 and carboplatin AUC5 plus oral capecitabine 1000 mg/m2 bd days 1–14, q4w (CTX) or intravenous epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 plus oral capecitabine 625 mg/m2 bd days 1–21, q3w (epirubicin, oxaliplatin and capecitabine [EOX]). Treatment continued until progression, intolerance or for a maximum of nine cycles. The primary endpoint was 1-year survival for patients treated with CTX. Results: Between June 2014 and January 2019, a total of 98 eligible patients were randomized. The 1-year survival rate was 34.7% (95% CI 21.8 − 47.9) with CTX and 36.7% (95% CI 23.6 − 50.0) with EOX. Progression-free survival and overall survival were 6.1 months (95% CI 5.5 − 7.1) and 9.8 months (95% CI 8.2 − 11.0) with CTX and 5.1 months (95% CI 4.3 − 7.0) and 10.2 months (95% CI 8.0 − 11.9) with EOX, respectively. Related grade 3 or 4 treatment-emergent adverse events (AEs) occurred in 86% of patients on CTX and 69% on EOX. Febrile neutropenia occurred in 31.4% of patients on CTX and 13.7% on EOX. Conclusions: First-line CTX showed insufficient efficacy and caused a high rate of febrile neutropenia. CTX could not, therefore, be recommended for further study. This trial adds to current knowledge of docetaxel combined with platinum and 5-FU: that the combination is associated with increased toxicity and its use should be

BackgroundThere are inconsistencies in the literature regarding the prevalence and assessment of chemotherapy-induced peripheral neuropathy (CIPN). This study explored CIPN natural history and its characteristics in patients receiving taxane- and platinum-based chemotherapy.Patients and methodsMulti-country multisite prospective longitudinal observational study. Patients were assessed before commencing and three weekly during chemotherapy for up to six cycles, and at 6,9, and 12 months using clinician-based scales (NCI-CTCAE; WHO-CIPN criterion), objective assessments (cotton wool test;10 g monofilament); patient-reported outcome measures (FACT/GOG-Ntx; EORTC-CIPN20), and Nerve Conduction Studies.ResultsIn total, 343 patients were recruited in the cohort, providing 2399 observations. There was wide variation in CIPN prevalence rates using different assessments (14.2-53.4%). Prevalence of sensory neuropathy (and associated symptom profile) was also different in each type of chemotherapy, with paclitaxel (up to 63%) and oxaliplatin (up to 71.4%) showing the highest CIPN rates in most assessments and a more complex symptom profile. Peak prevalence was around the 6-month assessment (up to 71.4%). Motor neurotoxicity was common, particularly in the docetaxel subgroup (up to 22.1%; detected by NCI-CTCAE). There were relatively moderately-to-low correlations between scales (rs = 0.15,p < 0.05-rs = 0.48 p < 0.001), suggesting that they measure different neurotoxicity aspects from each other. Cumulative chemotherapy dose was not associated with onset and course of CIPN.ConclusionThe historical variation reported in CIPN incidence and prevalence is possibly confounded by disagreement between assessment modalities. Clinical practice should consider assessment of motor neuropathy for neurotoxic chemotherapy. Current scales may not be all appropriate to measure CIPN in a valid way, and a combination of scales are needed.

Paclitaxel is a common chemotherapy drug associated with the development of chronic paclitaxel-induced peripheral neuropathy (PIPN). PIPN is associated with neuroinflammatory mechanisms in pre-clinical studies. Here, we evaluated for differential gene expression (DGE) in peripheral blood between breast cancer survivors with and without PIPN and for neuroinflammatory (NI) related signaling pathways and whole-transcriptome profiles from other experiments. Pathway impact analysis identified 8 perturbed NI related pathways. Expression profile analysis found 15 experiments having similar whole-transcriptome profiles of DGE related to neuroinflammation and PIPN. These findings suggest that perturbations in pathways associated with neuroinflammation are found in cancer survivors with PIPN.

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a significant and difficult to manage side effect of neurotoxic chemotherapies. Several risk factors for CIPN have been identified to date, but inconsistencies and methodological limitations exist in past research. Also, a limited number of potential risk factors has been investigated in the past.AimThe objective of this study was to assess the relative contribution of a wider range of risk factors in the development of CIPN.MethodsThis analysis used the 6-month data after starting chemotherapy from a larger prospective observational study on CIPN risk, prevalence, and quality of life. Patients were assessed at recruitment for possible CIPN risk factors, including prior history of neuropathies, current/past infectious diseases; neurotoxic medication history; personal and treatment characteristics; smoking history, alcohol use, and vegetable/fruit intake. Neuropathy was assessed at 6-months after starting chemotherapy with the neuropathy (motor/sensory) items of the NCI-CTCAE scale and the WHO criterion for neuropathy. Data on symptom burden were also collected.ResultsData were available from 255 patients from three cancer centers in Hong Kong, Singapore, and UK. The use of different scales did not always identify the same predictor variables. Key risk factors in multivariate regression models included older age (highest OR = 1.08, p < 0.01 with the WHO scale), chemotherapy (platinum-based chemotherapy had OR = 0.20-0.27 in developing CIPN compared to taxane-based chemotherapy), history of neuropathy (for motor CIPN only, OR = 8.36, p < 0.01), symptom burden (OR = 1.06, p < 0.05), number of chemotherapy cycles received (OR = 1.19-1.24, p < 0.01), and alcohol intake (OR = 0.32, p < 0.05). In univariate analysis, the use of statins was implicated with CIPN (p = 0.03-0.0

Purpose: Standard adjuvant chemotherapy for HER2-negative breast cancer consists generally in an anthracycline and taxane-based regimen (A+T). The TC (docetaxel and cyclophosphamide) regimen arises as a potential alternative, although individual randomized controlled trials (RCTs) could not demonstrate the non-inferiority of TC over A+T. This is a systematic review and meta-analysis of RCTs comparing 6 cycles of TC versus sequential A+T in the adjuvant treatment of HER2-negative breast cancer. Methods: A systematic literature search was performed to identify RCTs comparing TC versus A+T. Disease-free survival (DFS) and overall survival (OS) were assessed. Subgroup analyses of DFS according to hormone receptor status, lymph node involvement, and menopausal status were performed. Hazard ratios (HRs) and 95% confidence intervals (CI) for DFS and OS were extracted from each trial, and a pooled analysis was conducted using the random-effect model. The Higgins’ I-Squared Test was used to quantify heterogeneity. Results: Seven RCTs were included (12,741 patients). Overall, no difference was observed between TC and A+T in DFS (HR 1.08, 95% CI 0.96–1.20) and OS (HR 1.05; 95% CI 0.90–1.22). A trend favoring A+T was observed in hormone receptor-negative (HR 1.12, 95% CI 0.93–1.34) and N2 patients (HR 1.25; 95% CI 0.82–1.90). Emesis/vomiting, mucositis, thrombocytopenia and sensory neuropathy were significantly more frequent with A+T. Conclusion: As adjuvant treatment of HER2-negative breast cancer, sequential A+T regimen was associated with increased risk of toxicities and no clear survival benefit as compared to 6 cycles of TC. Higher-risk patients may benefit the most from A+T, whilst TC may be an efficacious and less toxic alternative for lower-risk patients., SCOPUS: re.j, DecretOANoAutActif, info:eu-repo/semantics/published

BackgroundPaclitaxel is one of the most commonly used drugs to treat breast cancer. Its major dose-limiting toxicity is paclitaxel-induced peripheral neuropathy (PIPN). PIPN persists into survivorship and has a negative impact on patient's mood, functional status, and quality of life. No interventions are available to treat PIPN. A critical barrier to the development of efficacious interventions is the lack of understanding of the mechanisms that underlie PIPN. Mitochondrial dysfunction has been evaluated in preclinical studies as a hypothesized mechanism for PIPN, but clinical data to support this hypothesis are limited. The purpose of this pilot study was to evaluate for differential gene expression and perturbed pathways between breast cancer survivors with and without PIPN.MethodsGene expression in peripheral blood was assayed using RNA-seq. Differentially expressed genes (DEG) and pathways associated with mitochondrial dysfunction were identified between survivors who received paclitaxel and did (n = 25) and did not (n = 25) develop PIPN.ResultsBreast cancer survivors with PIPN were significantly older; more likely to be unemployed; reported lower alcohol use; had a higher body mass index and poorer functional status; and had a higher number of lower extremity sites with loss of light touch, cold, and pain sensations and higher vibration thresholds. No between-group differences were found in the cumulative dose of paclitaxel received or in the percentage of patients who had a dose reduction or delay due to PIPN. Five DEGs and nine perturbed pathways were associated with mitochondrial dysfunction related to oxidative stress, iron homeostasis, mitochondrial fission, apoptosis, and autophagy.ConclusionsThis study is the first to provide molecular evidence that a number of mitochondrial dysfunction mechanisms identified in preclinical models of various types of neuropathic pain including chemotherapy-induced peripheral neuropathy are found in breast cancer survivor

Currently, the clinical utility of taxane-based drug formulations in castration-resistant prostate cancer (CRPC) is severely limited by acquired chemotherapy resistance, dose-limiting toxicities, and nonresponders. Therefore, approaches to improve taxane-based chemotherapy are desperately required. In this review, we highlight the strategies that aim to overcome these limitations, such as bypassing therapy resistance, targeted drug delivery, and adequate prediction of therapy response. The involvement of the apoptotic pathway, ABC transporters, the glucocorticoid receptor (GR) axis, androgen receptor (AR) splicing, epithelial plasticity, and cancer stem cells in mediating taxane-resistance are outlined. Furthermore, passive and active targeted nanomedicinal drug delivery strategies and the use of circulating tumor cells in predicting docetaxel responses are discussed. Finally, recent advances towards clinical translation of these approaches in CRPC are reviewed.

Context Biomarkers for the treatment of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed by clinicians to facilitate treatment decisions. Objective To review current prognostic and predictive biomarkers in mCRPC. Evidence acquisition We performed a nonsystematic review of the literature from 2004 to August 2016 by searching in Medline. Cross-matching references were used to search for additional articles. We reviewed clinical research and review articles written in the English language. Evidence synthesis Nomograms of prognostic factors (eg, albumin, lactate dehydrogenase) enable clinicians to estimate the prognosis of men with mCRPC. These prognostic tools may aid with when to trigger treatment, therapeutic monitoring, and follow-up. However, validated predictive biomarkers in mCRPC are still lacking. Androgen receptor (AR) splice variants (ie, AR-V7), gene fusions, and point mutations determined using liquid biopsies such as circulating tumor cells (CTCs) or cell-free DNA (cfDNA) are promising biomarkers that are the subject of ongoing research. Patient biomarkers (eg, neutrophil-to-lymphocyte ratio) are readily available and come with no extra cost but need further validation before their implementation in clinical practice. Conclusions Determination of AR-V7 in CTCs is a big step towards a more personalized treatment approach in mCRPC. Genomic characterization of liquid biopsies such as CTCs, cfDNA, and circulating RNA are noninvasive tools to further personalize treatment in prostate cancer. Clinical parameters are readily available, but are derived from retrospective studies and should be interpreted with care. Only by conducting biomarker-driven studies, rather than large one-size-fits-all trials, will we be able to improve prostate cancer treatment. Patient summary Several biomarkers are currently under investigation that may predict which patients will respond to specific therapies in the future of metastatic castration-resistant

The goal of this thesis was to improve current abilities in the management of taxane therapy using interventional and pharmacological approaches. Thereby aiming for providing patients with an optimally effective therapy, while reducing toxicity. This thesis sheds new light on factors influencing the pharmacokinetics and pharmacodynamics of the taxanes paclitaxel, docetaxel and cabazitaxel, further optimizing taxane therapy.

Androgen deprivation therapy (ADT) has been used in the treatment of metastatic prostate cancer since the first description of its hormonal dependence in 1941. In 2004, docetaxel chemotherapy became the mainstay of treatment in metastatic castration-resistant prostate cancer (mCRPC), following robust, albeit modest, survival benefit in two randomized phase 3 trials. The recently published CHAARTED trial was the first to show that combining ADT with docetaxel in men with hormone-naïve (hormone-sensitive) metastatic prostate cancer (mHSPC) yielded a remarkable overall survival benefit of 13.6 months as compared with ADT alone. In the current issue of The Lancet, James et al. report results of the STAMPEDE trial in men with high-risk locally advanced or metastatic prostate cancer initiating long-term hormone therapy. The combination of six cycles of docetaxel with ADT in men commencing long-term ADT demonstrated a similar OS benefit compared with standard of care (SOC) by a median of 10 months. Based on the consistency of the data and the firmness of the benefit provided, docetaxel in addition to ADT should be considered SOC for men with newly diagnosed mHSPC.

Introduction: The diagnosis of breast cancer during pregnancy (BCP) represents a unique challenge to the patient, her family and the treating physician. The proper management of this critical clinical situation is crucial, and requires a multidisciplinary approach. A proper understanding of the safety of chemotherapy during pregnancy is a vital step to avoid detrimental consequences on the mother and the fetus.Areas covered: The aim of this article is to review the available evidence on the safety of chemotherapy administration in managing BCP.Expert opinion: The rule of thumb of chemotherapy - avoiding first trimester exposure and starting therapy in the second trimester - can be considered applicable for classic agents that are used in managing pregnant breast cancer patients. Anthracycline-based regimens are considered the standard of care in managing BCP. Recently, a growing amount of data suggests the safety of taxanes during pregnancy. Pregnancy in cancer patients should be considered as "high risk": once the systemic treatment is initiated, regular fetal monitoring is highly recommended. Emerging data are available on the relative long-term safety secondary to anthracycline exposure during pregnancy. A continued monitoring of the health of individuals with prenatal exposure to chemotherapy into adulthood is recommended for the possible occurrence of long-term side effects., SCOPUS: re.j, info:eu-repo/semantics/published

type:Departmental Bulletin Paper, [Abstract] The prognosis of advanced cervical cancer remains poor. Recently, the significant activity of paclitaxel has been shown in advanced cervical cancers. We report a patient with advanced uterine cervical cancer who responded to neoadjuvant combination chemotherapy with taxanes and platinum. The patient was a 53-year old woman who presented with pollakisuria, lumbago, and pain in the anus and inguinal lesion, without genital bleeding. The findings indicated a clinical diagnosis of stage 4b disease with lung metastasis. We performed neoadjuvant combination chemotherapy with 7 courses of TC therapy (paclitaxel and carboplatin) and 7 courses of DP therapy (docetaxel and cisplatin) with a good effect., Mituhashi, Youji, Ohmura, Gen, Amano, Youko

QC 20140917

Current treatment of metastatic breast cancer (MBC) aims at achieving meaningful clinical responses, improved quality of life, long-term remissions, prolonged survival, and dares to hope for a cure in a small percentage of cases. This article will discuss both consensus and controversies in the management of MBC in the context of the new evolving breast cancer molecular classification. Hormonal therapy remains the mainstay of management of MBC Luminal A and B. Data is emerging on management of ErbB2-positive HR-positive MBC by combining hormonal manipulation and targeted anti-ErbB2 therapy and has recently received regulatory approval in Europe and USA. The optimal use and duration of single agent or combination chemotherapy is discussed. Data and controversies surrounding the use of newer agents such as nab-paclitaxel, ixabepilone, eribulin, and PARP inhibitors as well as trastuzumab is reviewed. Better understanding of pathophysiology has paved the way for the introduction of newer anti-ErbB2 agents such as lapatinib, pertuzumab, T-DM1 and neratinib. Controversies regarding bevacizumab and anti-angiogenesis are discussed. Bisphosphonates have significantly reduced skeletal related events and made significant improvements in the quality of life of patients with MBC. Newer anti-RANK Ligand antibodies show promising results. Significant advances in the understanding of molecular biology of breast cancer have been made and should lead to an improvement in the outcome of MBC. More possibilities of cure can become an attainable goal in the near future., Journal Article, Review, SCOPUS: re.j, info:eu-repo/semantics/published

Eribulin is a synthetic analog of halichondrin B, a non-taxane microtubule inhibitor extracted from the marine sponge, Halichondria okaida. It presents a novel mechanism of action and is active on cancer cells resistant to other antimicrotubule agents. It was granted approval in the USA and Europe for the treatment of heavily pretreated metastatic breast cancer. Early trials had shown activity in this setting with main toxicities being neutropenia and neuropathy in patients where quality of life is essential. Approvals were granted after a phase 3 trial demonstrated overall survival benefit in metastatic breast cancer previously treated with anthracyclines, taxanes, and capecitabine, in a setting where most treatments are failing to demonstrate a survival benefit. Recent data suggest that this survival benefit is also consistent in the elderly with no excess toxicity. Future strategies of eribulin are being tested in ongoing trials, evaluating this drug in earlier metastatic lines as well as in the adjuvant and the neoadjuvant settings., Journal Article, Review, SCOPUS: re.j, info:eu-repo/semantics/published

Taxanes are microtubule targeting agents (MTAs) and potent cytotoxic molecules recognized as highly effective chemotherapeutic agents. In large randomized clinical trials, taxane-based chemotherapies provided benefits in overall and disease-free survival, but they are accompanied by significant adverse effects. Thus the clinical utility of taxane therapy would be enhanced if there were companion diagnostic tests so that only the taxane-sensitive patients (about half of breast cancers) could be treated with this drug. Accumulating evidence indicates that microtubule associated proteins (MAPs) may be responsible for tumor cell resistance to taxanes. Our results indicate that MAP-tau functions as a prognostic factor in both the Yale cohort and the TAX 307 cohort with high MAP-tau expression associated with longer overall survival and TTP. Tau does NOT behave as a predictor of response to taxane-based chemotherapy since differences between low and high MAP-tau groups by treatment arm and response rate were not observed in the TAX 307 clinical trial cohort. Our data supports the use of MAP-tau as a prognostic marker, but does not support its use as a singular predictive factor for response to docetaxel. We have also evaluated the microtubule destabilizer, stathmin, and found high expression is associated with worse outcome. Since stathmin expression is useful in predicting survival, it may serve as marker to accurately select patients for current taxane-based or other anti-microtubule therapies in combination with a microtubule stabilizer such as MAP-tau., The original document contains color images.

Significant advances in cancer treatment have been achieved with novel targeted and state-of-the-art treatments. While the targeted treatments have received much attention in recent years, the more 'traditional' chemotherapeutic agents continue to play an important role in several malignancies. Former taxanes such as docetaxel and paclitaxel, with their broad anticancer activity, have contributed significantly to the improved treatment of a number of neoplastic diseases. Unfortunately, until now, the achievements obtained with these compounds have been mitigated by clinical limitations such as acquired or intrinsic resistance of tumors, poor CNS activity, allergic reactions and unfavorable toxicity profiles. Larotaxel (RPR 109881A) is a taxane analogue with a broad spectrum of activity and different toxicity profile and with the possible advantages of surpassing some mechanisms of resistance and penetrating into the CNS. The development path of this drug, its core clinical data and future treatment perspectives are discussed in this article., SCOPUS: re.j, info:eu-repo/semantics/published

Over the last decades, the introduction of several new agents into clinical practice has significantly improved disease control and obtained some, albeit rare, survival benefits in metastatic breast cancer (MBC). Despite these results, the choice of treatment for the majority of patients is still empirically based, since the only two predictive factors with level 1 evidence for clinical use are hormonal receptor status for endocrine therapy and HER-2 status for trastuzumab therapy. Important improvements in the endocrine therapy of both pre- and postmenopausal women with hormone-responsive disease have been achieved. For premenopausal women, ovarian function suppression with luteinizing hormone-releasing hormone analogs combined with tamoxifen has become the standard treatment, although aromatase inhibitors plus ovarian function suppression are under evaluation. In postmenopausal patients, aromatase inhibitors have proved to be superior to standard endocrine therapies in either first- or second-line treatment and a novel antiestrogen compound, fulvestrant, has been introduced in clinical practice. Chemotherapy remains the treatment of choice for hormone unresponsive or resistant patients. Anthracyclines and taxanes have been used either alone or in combination as first-line chemotherapy, but with the more frequent use of these agents in the adjuvant setting, new standards are needed for first-line chemotherapy, and new and more efficacious treatments are required. In the subgroup of patients with tumors that overexpress HER-2, the use of trastuzumab alone or in combination with chemotherapy has modified the natural history of these tumors, even if only about one out of two patients obtains a clinical response. In this review we summarize the main achievements and the currently available treatment options for patients with MBC., Journal Article, Review, info:eu-repo/semantics/published

In recent decades, the use of adjuvant systemic therapies for early breast cancer has increased extensively and has most likely contributed to the decline in breast cancer mortality observed in the U.S. and in some European countries. The last few years have witnessed accelerated progress in the treatment of early breast cancer, with the introduction of taxanes and aromatase inhibitors and, most impressively, trastuzumab to the adjuvant portfolio. When compared with anthracycline-based regimens, the addition of taxanes to treatments for patients with node-positive breast cancer has shown benefits in disease-free survival and, in some trials, in overall survival; however, these drugs are not yet universally accepted as standard treatment. Significant improvements in endocrine therapy in both pre- and postmenopausal patients with endocrine-responsive disease have been made. In the postmenopausal setting, aromatase inhibitors have shown superiority over tamoxifen in a direct comparison upfront or when given in sequence after 2-5 years of tamoxifen, but the optimal modality of administration remains unclear. For premenopausal women, ovarian function suppression with luteinizing hormone-releasing hormone analogues combined with tamoxifen has generated similar results to cyclophosphamide, methotrexate, 5-fluorouracil (CMF)-based regimens. Recently, trastuzumab has had a dramatic impact on the evolution of human epidermal growth factor receptor 2 (HER-2)-positive early breast cancer treated with standard adjuvant modalities; specifically, relapses, including distant relapses, have been halved. In this review, we summarize these main achievements, discuss the currently available adjuvant treatment options for breast cancer patients, and emphasize the need for more efficient translational research to improve individual treatment tailoring., Journal Article, Review, info:eu-repo/semantics/published

Purpose: The incidence of bronchioloalveolar carcinoma (BAC) has risen steadily over the last decades along with the increasing frequency of adenocarcinomas. BAC is relatively resistant to commonly used chemotherapy regimens. A phase II study with single agent paclitaxel in patients with stages IIIB, IV or recurrent BAC was performed. Experimental design: Patients with BAC with at least one target bidimensionally measurable lesion staged as unresectable stages IIIB, IV or recurrent disease, not previously irradiated; ECOG performance status 0–2; life expectancy greater than 3 months; age range between 18 and 75, received paclitaxel at a dose of 200 mg/m2 i.v. as 3 h continuous infusion on day 1 every 21 days. Treatment was continued until progression or up to a maximum of six cycles. Results: Nineteen patients were eligible. Median number of cycles was 3 (range 0–6); 35% of patients received the planned six cycles of chemotherapy. One patient died of unrelated cause before the start of treatment. Both hematological and non-hematological toxicities were generally mild. Only one partial response (PR) was observed among the 18 eligible patients who started protocol treatment, with a response rate of 5.6% (95% CI: 0.1–27.3%). After an independent review, two PR were confirmed, for a response rate of 11.1% (95% CI: 1.4–34.7%); nine patients had stable disease (50.0%), three patients had progressive disease (11.1%) and four patients were not assessable (22.2%). Median survival was 8.6 months (95% CI: 5.8–14.5) and 1-year survival was 35.0% (95% CI: 14.1–55.8). Median progression free survival for all patients was 2.2 months (95% CI: 1.5–6.0). The study was terminated due to the low response rate. Conclusions: Paclitaxel

Since the introduction of docetaxel, research has focused on various approaches to overcome treatment limitations and improve outcome. This review discusses the pharmacological attempts at treatment optimisation, which include reducing interindividual pharmacokinetic and pharmacodynamic variability, optimising schedule, route of administration, reversing drug resistance and the development of structurally related second-generation taxanes.

The 2003 St. Gallen consensus panel divided the many available adjuvant chemotherapy (CT) regimens into those with "standard efficacy" (ACx4, CMFx6) and those with "superior efficacy" (FA(E)Cx6, CA(E)Fx6, A(E)-->CMF, TACx6, ACx4--> paclitaxel (P)x4 or docetaxel (D)x4) but also greater complexity, toxicity and cost. This paper will summarize the latest information on long-term side effects of the "superior" regimens and 5-year benefits reported in taxane trials, including those of a "new" sequential regimen, FECx3--> docetaxelx3. Rapidly expanding evidence of marked heterogeneity in the magnitude of CT benefits according to the tumour oestrogen receptor (ER) status, a claim made for many years by IBCSG investigators, will be reviewed; it will lead to the conclusion that a revolution needs to take place in the way oncologists think about the CT added value and design adjuvant clinical trials. The conclusions proposed to the 2005 St. Gallen consensus panel are that: adequately dosed anthracycline-based CT regimens remain an acceptable standard for many women; a lower threshold for using taxanes in sequence or combination with anthracyclines (A) is justified in the presence of an ER-negative or low-ER tumour status, other aggressive biologic features (such as HER-2 overexpression), fear about A-induced cardiotoxicity; no recommendation can yet be made as far as the optimal taxane-A regimen, the best taxane or the best taxane schedule., Journal Article, Review, info:eu-repo/semantics/published

Studies suggest that p53 mediates responsiveness to chemotherapy. The development of p53 GeneChip technology has made high-throughput mutation analysis more feasible. In an ongoing multi-institutional prospective trial that is not supported by this award, breast cancer patients receiving neoadjuvant chemotherapy have serial response assessments and tumor sampling for research purposes. The project that is supported by this award involves analyzing the banked tumor specimens for p53 mutations using the GeneChip method. We hypothesize that p53 status of the primary tumor will predict response to anthracycline-based and taxane-based chemotherapy given at different times in the same patient. A yeast-based functional assay will examine the impact of specific p53 mutations upon transactivation function. Progress to date includes optimizing the GeneChip method of p53 mutation analysis for core biopsy specimens, successful scaling down of the DNA requirements for such assays allowing evaluation of small tumor biopsy samples, optimizing methods for p53 amplification within 1-2 large fragments so that SSCP and sequencing analysis will be feasible despite the small amount of DNA available, initiating p53 mutation analysis upon the study samples, and adaptation and successful implementation of the yeast-based functional assay for assessing the effect of specific p53 mutations.

__Abstract__ Over forty years ago, samples of the Taxus brevifolia, the pacific yew tree, were screened by the National Cancer Institute (NCI) for anticancer activity. Screening indicated that an extract from the tree possessed activity against tumour cell lines. Paclitaxel the active compound of the extract, was isolated in its pure form in 1969. The mechanism of action was not described until 1979 when Schiff and Horwitz discovered its unique mechanism of cytotoxicity. In contrast to other mitotic agents, paclitaxel and docetaxel promoted the assembly of tubulin and stabilised the resulting microtubules. Clinical studies with paclitaxel started in 1983. At the same time French researchers produced semisynthetic derivatives of baccatin III, an extract from the needles of the European yew Taxus baccata, and modified it with a chemically synthesised side chain. Docetaxel emerged from these efforts and entered clinical trials in 1990. Drug vehicle, drug-interactions, tissue penetration and age are all factors affecting drug pharmacokinetics, and are the focus of this thesis.

SCOPUS: ar.j, info:eu-repo/semantics/published

In this thesis the results of clinical studies with new chemotherapeutic agents and pharmacokinetic studies on taxanes in breast cancer patients are reported. In metastatic breast cancer, endocrine and cytotoxic treatment often result in objective tumor responses, associated with relevant relief of symptoms. At present, however, metastatic breast cancer is still considered to be incurable even despite agressive multi-modality treatment options. Chemotherapy for metastatic breast cancer should therefore aim at a maximum of palliation and prolongation of life, at the cost of a minimal of toxicity.

The application of immunoaffinity chromatography for the purification of Taxus plant and cell extracts prior to the HPLC analysis is described. Polyclonal antibodies raised against 10-deacetylbaccatin III (10-DAB III), paclitaxel's main precursor in plant, were characterised by enzymed-linked immunosorbent assay. Immunoglobulins from selected antisera were immobilised on CNBr-activated Sepharose 4B. The immunoaffinity column was used for the purification of plant and plant cell culture extracts prior to their analysis by HPLC. Immunoaffinity chromatography enabled the selective concentration of taxoids and enhanced sample clean-up. © 2002 Elsevier Science B.V. All rights reserved., SCOPUS: cp.j, info:eu-repo/semantics/published

Oral capecitabine is a useful chemotherapy for metastatic breast cancer, both as monotherapy and in combination with other cytotoxic drugs. The proven activity of capecitabine has provided the rationale to explore its use earlier in the course of the disease and in combination with other agents, particularly those known to further upregulate thymidine phosphorylase (TP) concentrations in tumor tissue. The efficacy and safety of capecitabine monotherapy compares favorably with cyclophosphamide/methotrexate/5-fluorouracil in chemotherapy-naïve patients and with paclitaxel in anthracycline-pretreated patients. Therefore, for patients whose disease has progressed during or following anthracycline treatment, but for whom capecitabine/docetaxel combination therapy or taxane monotherapy is not appropriate, capecitabine monotherapy is an attractive alternative to established i.v. treatments. In combination, capecitabine plus paclitaxel, which further upregulates TP in tumor tissue, has demonstrated high activity in two phase II studies in advanced/metastatic breast cancer. Similarly, combination with vinorelbine showed promising activity in pretreated metastatic breast cancer patients, and triple combinations with an anthracycline and a taxane or cyclophosphamide have proven to be highly active. In the future, capecitabine may be combined with novel biologic agents, such as trastuzumab and bevacizumab; the former combination has already shown encouraging results in a pilot trial. Confirmatory studies for many of these combinations and phase III trials versus standard therapy are now warranted., SCOPUS: cp.j, info:eu-repo/semantics/published

The central objective of this investigation was to synthesize and test a novel class of water soluble taxol analogs for potential application in breast cancer chemotherapy, with particular emphasis on overcoming the problem of taxol-resistance that frequently encountered in clinical therapy. We hypothesized that the proposed novel taxol analogs containing both effective functional groups at side chain and strong water soluble moieties at C7 position should be able to circumvent P-glycoprotein mediated multidrug resistance and to enhance the effectiveness in killing taxol-resistant breast cancer cells. We have made significant progress in this research project. Three key intermediate compounds have been successfully synthesized and identified, whereas the synthesis of the proposed taxol analogs is nearing completion. The final intermediate compound has also been made and detected. The feasible and practicable synthetic routes have been established in this project for preparation of these extremely important intermediate compounds that will essentially be used for the successful synthesis of the proposed water soluble taxanes. All these encouraging results will greatly contribute to the development of water soluble taxol analogs for overcoming taxol-resistance in human breast cancers. If this project is successful, the clinical benefits to breast cancer patients could be enormous.

A Taxus baccata cell line has been characterized for growth, nutrient uptake, taxane production and for GGPP synthase activity. The enzyme is extracted by inclusion of non-ionic detergent and its activity parallels taxane production for the first three days. The enzyme activity reaches its peak at day 3 of culture growth, while total taxane formation rises until day 9, when the maximum taxane accumulation in the cells is observed (~0.004% dry wt). After this day the taxane excretion in the medium increases, reaching its maximum at day 19., SCOPUS: ar.j, info:eu-repo/semantics/published

This thesis outlines work towards the optimisation and production of taxadienone, a useful precursor to the low oxidation state taxanes and a member of the taxane family of natural products, through synthetic chemistry. Chapter I Introduces the taxane family of natural products, their biosynthesis, biological activities and extraction. Chapter II describes our synthesis of taxadienone, using carbon building blocks from a sustainable source. We started our work with the formation of the C ring via an acid catalysed cyclisation of a polyene derived from the natural product, E/Z farnesol. A single isomer of farnesol was also used to study its effect on the diastereoselectivity of the cyclised product. Cyclisation was followed by the use of a novel indium-Reformatsky reaction to form a -lactone which subsequently underwent decarboxylation to form a tetra-substituted diene. This was followed by the well-established Diels-Alder approach to construct taxadienone. Chapter III provides an experimental section that gives detailed procedures and full characterisation data for the novel compounds discussed in the results and discussion.